Fruit extracts and extract formulations of canarium odontophyllum as actives and related invention embodiments

Abstract

Method for producing an extract or extract formulation of the fruit of Canarium odontophyllum comprising or consisting of the following steps: (i) providing fruit material from Canarium odontophyllum , wherein said fruit material essentially consists of the endocarp of the seeds of Canarium odontophyllum, (i-a) optionally drying the fruit material provided in step (i), (ii) extracting the fruit material provided in step (i) or (i-a) with a mixture essentially consisting or consisting of water and an alcohol having 1 to 3 carbon atoms or consisting water and acetonitrile, (iii) optionally partially or fully removing the alcohol having 1 to 3 carbon atoms of step (ii), and optionally adding an organic solvent of medium polarity to said aqueous residue and extracting the aqueous residue with said organic solvent or a supercritical solvent, such as supercritical carbon dioxide thereby obtaining an enriched extract, (iv) optionally mixing the extract obtained in step (ii) or the enriched extract obtained in step (iii) with one or more solid carrier substances, (v) optionally drying the enriched extract obtained in step (iii) or the mixture obtained in step (iv), preferably by spray-drying or freeze-drying., and related invention embodiments, especially for use in the treatment of PDE2 and/or PDE5 related diseases, and related invention embodiments.

1 . A method for producing an extract or extract formulation of the fruit of  Canarium odontophyllum  comprising:
 (i) providing fruit material from  Canarium odontophyllum , wherein said fruit material essentially consists of the endocarp of the seeds of  Canarium odontophyllum,      (ii) extracting the fruit material provided in step (i) with a mixture consisting essentially of water and an alcohol having 1 to 3 carbon atoms or consisting of water and acetonitrile.   
     
     
         2 . The method according to  claim 1 , wherein the fruit material provided in step (i) comprises 85 wt. % or more of woody endocarp of  Canarium odontophyllum.    
     
     
         3 . The method according to  claim 2 , wherein the fruit material provided in step (i) comprises less than 15 wt. % of seeds of  Canarium odontophyllum.    
     
     
         4 . The method according to  claim 3 , wherein the ratio by weight of the total amount of seedless woody endocarp of  Canarium odontophyllum  to the total amount of seeds of  Canarium odontophyllum  is greater than 5.1:1. 
     
     
         5 . An extract or extract formulation obtainable by a method according to  claim 1 . 
     
     
         6 . Extract or extract formulation obtainable by a method comprising or consisting of the following steps:
 (a-i) providing fruit material from  Canarium odontophyllum , wherein said fruit material consists essentially of the endocarp of the fruits of  Canarium odontophyllum,      (a-ii) optionally drying the fruit material provided in step (a-i),   (a-iii) extracting the fruit material provided in step (i) or (i-a) with a mixture essentially consisting or consisting of water and an alcohol having 1 to 3 carbon atoms or consisting of water and acetonitrile, preferably with a mixture of ethanol and water, wherein the total volume ratio (v/v) of said alcohol:water is in the range of 1:30 to 30:1, preferably in the range of 1:10 to 10:1, more preferably in the range of 1:5 to 5:1, even more preferably in the range of 1:2 to 2:1, yet more preferably in the range from 1.2:1 to 1:1.2, and most preferably in the range of 1:1,   (a-iv) optionally partially or fully removing the alcohol having 1 to 3 carbon atoms or acetonitrile of step (ii), preferably at a temperature below 80° C., more preferably in the range from 15 to 60° C., thereby obtaining an aqueous residue, and   optionally adding an organic solvent of medium polarity to said aqueous residue and extracting the aqueous residue with said organic solvent or a supercritical solvent, such as supercritical carbon dioxide wherein the organic solvent is preferably selected from the group consisting of n-butanol, iso-butanol, 2-butanone, 3-pentanone, methyl n-propyl ketone, methyl iso-propyl ketone, methyl isobutyl ketone, methyl isoamyl ketone, methyl-t-butyl ether, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, ethyl propanoate and ethyl butanoate or a mixture thereof, and subsequently separating the organic layer comprising the organic solvent of medium polarity,   thereby obtaining an enriched extract,   (a-v) preferably mixing the extract obtained in step (ii) or the enriched extract obtained in step (iii) with one or more solid carrier substances, preferably one or more solid carrier substances selected from the group consisting of maltodextrins, silica, talc, lactose, sorbitol, mannitol, dextrose, sucrose, starches, gum acacia, calcium phosphate, orally acceptable stearate salts, preferably magnesium stearate, alginates, tragacanth, gelatins, calcium silicates, cellulose and cellulose derivatives, preferably amorphous cellulose, microcrystalline cellulose or methyl cellulose, polyvinylpyrrolidones, and propylhydroxybenzoates, and   (a-vi) optionally drying the enriched extract obtained in step (a-iv) or the mixture obtained in step (a-v), preferably by spray-drying or freeze-drying.   
     
     
         7 . A method of inhibiting phosphodiesterase activity comprising administering an effective amount of an extract of fruit material of the fruit of  Canarium odontophyllum , wherein the fruit material comprises one or more pyrenes. 
     
     
         8 . The method according to  claim 7 , wherein the fruit material from  Canarium odontophyllum  comprises 85 wt. % or more of the woody endocarp of fruits of  Canarium odontophyllum  and less than 15 wt. % of seeds of  Canarium odontophyllum , based on the total amount of fruit material. 
     
     
         9 . The method according to  claim 7 , further including prophylactic and/or therapeutic treatment of conditions related to the modulation of phophodiesterase 5 (PDE5 or PDE-V) and phosphodiesterase 2 (PDE2 or PDE-II) in the mammal body, especially in the human body, especially in a prophylactic and/or therapeutic treatment to induce vascular smooth muscle relaxation (PDE5) or to improve pulmonary conditions (PDE5), or prophylactic and/or therapeutic treatment in the case of male and female sexual dysfunction (PDE5), or for the prophylactic and/or therapeutic treatment of acute respiratory distress syndrome (PDE5) or in order to enhance cognition (PDE2) in mammals, preferably in human beings. 
     
     
         10 . A pharmaceutical composition, preferably an orally administrable pharmaceutical composition, comprising
 an effective amount of an extract obtained by a method according to  claim 1  for use in the prophylactic and/or therapeutic treatment of conditions related to the modulation of phophodiesterase 5 (PDE5 or PDE-V) and phosphodiesterase 2 (PDE2 or PDE-II) in the mammal body, especially in the human body, especially in a prophylactic and/or therapeutic treatment to induce vascular smooth muscle relaxation (PDE5) or to improve pulmonary conditions (PDE5), or prophylactic and/or therapeutic treatment in the case of male and female sexual dysfunction (PDE5), or for the prophylactic and/or therapeutic treatment of acute respiratory distress syndrome (PDE5) or in order to enhance cognition (PDE2) in mammals, preferably in human beings.   
     
     
         11 . The pharmaceutical composition according to  claim 10 , further comprising one or more additional pharmacologically active compound preferably selected from the group of
 (i) phosphodiesterase inhibitors,   (ii) phosphodiesterase inhibitors 5, and   (iii) phosphodiesterase inhibitors 2.   
     
     
         12 . The pharmaceutical composition according to  claim 11  wherein, in each case based on the total weight of the composition,
 the total quantity of phosphodiesterase inhibitors is in the range of from 0.005-10% by weight, preferably in the range of from 0.05-5% by weight and more preferably in the range of from 0.5-2.5% by weight. 
 
     
     
         13 . The composition according to  claim 10 , wherein said composition is in a form selected from the group consisting of orally consumable granules, tablets, pills, capsules, pellets, syrups, powders, solutions, and dispersions. 
     
     
         14 . The method according to  claim 1 , further comprising:
 (i-a) drying the fruit material provided in step (i) prior to step (ii).   
     
     
         15 . The method according to  claim 1 , further comprising:
 (iii) partially or fully removing the alcohol having 1 to 3 carbon atoms or the acetonitrile of step (ii) to yield an aqueous residue.   
     
     
         16 . The method according to  claim 15 , further comprising:
 adding an organic solvent of medium polarity to said aqueous residue and extracting the aqueous residue with said organic solvent or a supercritical solvent, such as supercritical carbon dioxide, thereby obtaining an enriched extract.   
     
     
         17 . The method according to  claim 16 , further comprising:
 (iv) mixing the extract obtained in step (ii) or the enriched extract obtained in step (iii) with one or more solid carrier substances.   
     
     
         18 . The method according to  claim 17 , further comprising:
 (v) drying the enriched extract obtained in step (iii) or the mixture obtained in step (iv), preferably by spray-drying or freeze-drying.   
     
     
         19 . The method according to  claim 1 , wherein the fruit material provided in step (i) comprises 90 wt. % or more of woody endocarp of  Canarium odontophyllum  and less than 12 wt. % of seeds of  Canarium odontophyllum.    
     
     
         20 . The extract or extract formulation according to  claim 5  showing vasodilator activity, including at least PDE 5 or PDE 2 inhibition activity.